Method for treating an acute myeloid leukemia

a myeloid leukemia and acute treatment technology, applied in the field of acute treatment of acute myeloid leukemia, can solve the problems of a large disease recurrence, poor prognosis of patients harboring calm-af10 fusion, and the ineffective treatment of patients with calm-af10 fusion by standard chemotherapeutic strategies

Pending Publication Date: 2022-03-31
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]Another aspect described herein is a method of administering to the subject an effective amount of 5-fluoro-2-(6-fluoro-2-methyl-1H-benzo[d]imidazol-1-yl)-N4-[4-(trifluoromethyl)phenyl]pyrimidine-4,6-diamine or a pharmaceutically acceptable salt or pharmaceutical composition thereof in combination with an effective amount of one or more chemotherapeutic

Problems solved by technology

Disease recurrence is a major problem in the treatment of AML.
Standard chemotherapeutic strategies are often not very effective in treating patients with CALM-AF10 fusions.

Method used

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  • Method for treating an acute myeloid leukemia
  • Method for treating an acute myeloid leukemia
  • Method for treating an acute myeloid leukemia

Examples

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example 1

[0230]Immunodeficient mice (NRG-SGM3) were injected with the P31-Fujioka cell line. Ten days after injection, engraftment of P31 cells in mice was confirmed by flow-cytometric assessment of the human CD45 marker (data not shown). One cohort of mice was orally administered Compound 1 and an age and engraftment matched hohort was administered vehicle control. The results are illustrated in FIG. 1, which shows a survival curves for the Compound 1 vs vehicle treated animals (n=5 mice per group, *P<0.002). The results indicate that treatment with Compound 1 significantly delayed the latency of disease in mice compared to the control.

example 2

[0231]The following study was conducted in a mouse model of acute myeloid leukemia (AML) based on intravenous (IV) injection of human MOLT-4-AML cells into male non-obese diabetic (NOD) severe combined immunodeficiency (SID) mice. MOLT-4 cells are CD3 positive. The NOD-SCID mice were obtained from Jackson Laboratory, Bar Harbor Me.

[0232]Male NOD-SCID mice were inoculated with MOLM13 human AML tumor cells from ATCC (5×106 cells in 200 μL PBS) by intravenous (IV) injection of 0.2 ml / mouse. Three days after tumor inoculation, mice were randomized into four groups of five mice per group, and each group was dosed as follows once each day: (Group 1) orally administered vehicle (0.5% HPMC), (Group 2) orally administered 12.5 mg / kg of Compound 1 in HPMC, (Group 3) orally administered 10 mg / kg of Compound 2 in HPMC, and (Group 4) orally administered a combination of 12.5 mg / kg of Compound 1 and 10 mg / kg of Compound 2 in HPMC for up to 75 days.

[0233]Results of the study are shown in FIGS. 2-5...

example 3

[0234]Male NOD-SCID mice were inoculated with MOLT human acute lymphoblastic leukemia (ALL) tumor cells from ATCC (1×107 cells in 200 μL PBS) by intravenous (IV) injection of 0.2 ml / mouse. Seven days after tumor inoculation, mice were randomized into seven groups of five mice per group, and each group was dosed as follows: (Group 1) orally administered vehicle of 0.5% HPMC and 0.1% Tween 80 daily, (Group 2) orally administered 10 mg / kg Compound 1 twice per week, (Group 3) orally administered 10 mg / kg Compound 2 daily, (Group 4) administered 1 mg / kg doxorubicin by intraperitoneal (IP) injection once per week, (Group 5) administered 0.5 mg / kg doxorubicin by IP injection once per week, (Group 6) administered 50 mg / kg Ara-C twice per week by IP injection, and (Group 7) administered 70 mg / kg Ara-C by IP injection once per week.

[0235]The resulting survival curves of the seven groups of mice from that study are shown in FIG. 6. As shown in FIG. 6, the maximum number of days of survival of ...

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Abstract

An aspect described herein includes a method for treating acute myeloid leukemia (AML) in a subject in need thereof comprising, administering to the subject an effective amount of a small molecule tubulin polymerization inhibitor compound. More particularly, another aspect described herein includes a method for treating acute myeloid leukemia in a subject in need thereof comprising, administering to the subject an effective amount of the small molecule tubulin polymerization inhibitor compound described herein in combination with a chemotherapeutic agent.

Description

INTRODUCTION[0001]Described herein is a method for treating an acute myeloid leukemia (AML) in a subject in need thereof comprising, administering to the subject an effective amount of a small molecule tubulin polymerization inhibitor compound. More particularly described herein is a method for treating an AML in a subject in need thereof comprising, administering to the subject an effective amount of a small molecule tubulin polymerization inhibitor compound alone or in combination with a chemotherapeutic agent.BACKGROUND[0002]Disease recurrence is a major problem in the treatment of AML. Elderly patients with p53 mutant mediated AML are at an extremely high risk of relapse, particularly those having complex karyotype (60-80%) and therapy-related AML (30%) in whom mutations of the tumor suppressor p53 occur frequently (Nishida Y, et al.,; The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cel...

Claims

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Application Information

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IPC IPC(8): A61K31/506A61K31/437A61P35/02
CPCA61K31/506A61P35/02A61K31/437A61K31/4184A61K31/407A61K45/06A61K2300/00
Inventor WEETALL, MARLA L.DESHPANDE, ANIRUDDHA JAYANTBARBOSA GUERRA, KARINA OFELIA
Owner SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INST
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